Diversification of readily accessible natural products and related compounds for drug development is a frontier goal in the 21st century. The novel scaffolds provided by such compounds, often rich with stereocenters, confer desirable biological properties and selective modes of action. Current synthetic methods are limited in their ability to introduce new functionality onto organic frameworks and as a result, these structures remain underutilized as drug candidates. Nature routinely uses sustainable iron-based P450 enzymes that oxidize sp3-hybridized C-H bonds (i.e. aliphatic, allylic, and benzylic) to introduce functionality onto complex molecular scaffolds, often with exquisite site-, chemo-, and stereoselectivity. This proposal seeks to develop catalysts that achieve enzyme-like selectivity for sp3 C-H oxidation, amination, alkylation, and halogenation reactions with the high substrate generality and operational ease characteristic of small molecule catalysis. These catalysts will employ iron and manganese, highly abundant, non-toxic, and relatively unexplored metals that present the exciting opportunity to discover reactivity that is orthogonal to extensively explored noble metal catalysts (Rh, Ru). To achieve this goal we will contribute novel catalysts and design strategies that evaluate control elements like electronics, chirality, and sterics for non-heme iron complexes (Fe(PDP)) that have already demonstrated the ability to effect preparative and predictably selective aliphatic C-H oxidations in complex molecule settings. These novel catalysts will address significant outstanding problems in aliphatic C-H oxidation such as chemoselectivity (tolerance of more electron rich unsaturated and heteroatom functionality), enantioselectivity, and achieving alternate modes of site-selectivity. We will continue to contribute novel catalyst platforms for selective C(sp3)-H aminations and alkylations that exploit the isoelectronic nature and mechanistic similarities of metal nitrenes and carbenes with metal oxos. The observed biomimetic reactivity of Fe(PDP) will be further explored to achieve stereoselective halogenations of aliphatic 3o C-H sites. Additionally, current catalysts will be refined to increase catalysts lifetimes. Collectively, we expect these aliphatic, allylic, and benzylic C-H functionalization reactions to enable the rapid synthesis and diversification of complex biologically relevant molecules that were otherwise inaccessible as pharmaceutical scaffolds. Additionally, we will continue refine our mathematical model, which quantitatively correlates the electronic, steric, and stereoelectronic properties of a substrate to site-selectiviy as a function of catalyst, via addition of new substrate classes (arenes, olefins, heterocycles, amines, ethers). The model will also be explored for its ability to inform catalyst design. The fundamental knowledge that will be gained from these studies will serve to redefine the physical organic properties of inert C-H bonds and will inform future catalyst and reaction designs.